Nucleoside triphosphates (NTPs) are substrates for numerous NTP-dependent enzymes within the body, and thus are crucial for a wide variety of biological processes. NTP mimetics would therefore be ideal candidates for chemical genetics programmes, to perturb intracellular processes with exquisite precision by the inhibition of selected proteins. We believe that replacement of the ~,y-pyrophosphate moiety of an NTP with a monosaccharide may still lead to favourable enzyme binding but lead to inhibition. Replacement of the a-phosphate group with a triazole linker would facilitate cell permeability by removing any remaining charge, as well as increase stability of the mimetic. Triazoles can be formed via the Cu(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of azides and terminal alkynes. A series of propargyl glycosides of various monosaccharides have been synthesised, in most cases possessing anomeric purity, and reliable protocols developed. A number of 5'azido nucleosides have also been synthesised, and coupling reactions carried out to obtain a library of 45 novel sugar-triazole-nucleosides. These compounds have been tested as potential inhibitors of the type III pantothenate kinase from Bacillus anthracis and one potent inhibitor discovered with a Kj of 164 p.M. This shows that the inhibitor binds approximately three times more tightly in the active site than the natural substrate ATP (Km = 475 M).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:492498 |
| Date | January 2008 |
| Creators | Rowan, Andrew Stephen |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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